Ischemic heart disease or myocardial ischemia is characterized by a significant drop of the blood supply to the heart muscle, the necessary oxygen and nutrient levels thereby decreasing. The most common cause of myocardial ischemia is due to occlusion of the coronary arteries as the result of an atherosclerotic process, the risk of which increases with age, in smokers, in subjects with hypercholesterolemia, diabetes and hypertension, and it is more common in male subjects.
Coronary occlusion results in the onset of ischemic necrosis or myocardial infarct, the incidence of which is directly related to the degree of oxygen and nutrient deprivation in the tissue. In the case of transient ischemia, subsequent reperfusion of the myocardium is directly associated with a spread of the myocardial necrosis referred to as lethal reperfusion injury.
Under hypoxia, cardiomyocytes are dependent on glycolysis as energy metabolism. The transport of lactic acid produced as a glycolysis byproduct is necessary for maintaining the cell viability and is carried out through lactate transporters called MCT-1 and MCT-4, the association of the latter with the protein called CD147 (also called Basigin or EMMPRIN (Extracellular Matrix Metalloproteinase Inducer)) having been described (Halestrap et al. 1999. Biochem J; 343: 281-299). Both MCT and EMMPRIN are overexpressed in ischemia in neuronal and heart cells (Zhang et al. 2005; J. Neurosc. Res. 79: 139-145). In the case of MCTs, overexpression is related to a protective effect against lactate build up. In the case of EMMPRIN, the effect is still unknown due to its interaction with other proteins, the process being extremely complex.
There are compounds described in the literature that have the capacity to reduce damage caused by cardiac ischemia. The use of nitrates (Pfister M et al. Heart 80 (4): 365-9), beta-blocking compounds (O'Rourke S T. Am J Pharm Educ, 2007; 71 (5): 95) (acebutolol or metoprolol) and agents that reduce hypertension has been described. Likewise, nitric oxide could also be used as a cardioprotective agent, because its efficacy has been verified through its impact in different mechanisms (West M B et al. Circulation. 2008; 118:1970-8. Lin J, et al., Circulation 2009; 120:245-54), including the use of substances such as propofol, which increase the production thereof in ischemia followed by reperfusion (Sun Hai-yan et al. Chin. Med. J 2009; 122: 3048-54). However, NO has a dual effect due to the fact of its significant involvement in oxidative stress associated with cardiac damage taking place during myocardial infarct (Liu Y H et al. American journal of physiology 2005; 289:H2616-2623), and to the fact that a significant increase of its production associated with an increase of cardiac damage in humans has been detected (Mungrue I N et al. J Clin Invest 2002; 109:735-743), whereas the use of NOS inhibitors such as L-NAME have been evaluated in various studies with at least promising, although not conclusive, results (Cotter G et al. European heart journal 2003; 24:1287-1295), suggesting that the effect of NO on the heart may be related to the time in which and the dose at which this factor occurs.
In relation to the effect of NO as a cardioprotective agent, it is important to stress the effect of the so-called ischemic pre-conditioning, a phenomenon that consists of the occurrence of repeated ischemia processes of a short duration, as a result of which the heart is capable of successfully tolerating the following prolonged ischemic processes after reperfusion. Among the different factors inducing the pre-conditioning process, NO is one of them, its efficacy in the cardioprotective process having been demonstrated (Xuan Y T et al. Circulation. 2007; 116: 535-44; West M B, et al. Circulation. 2008; 118:1970-8), and although various candidates associated with NO production in the process have been described, it is necessary to continue progressing in the in-depth knowledge of the cardioprotection exerted by this factor.
Despite the fact that compounds have been described for preventing or treating the symptoms associated with ischemia/reperfusion, there is a need to develop new compounds for reducing cardiac damage after ischemia followed by reperfusion that are more efficient than those described in the state of the art.